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Abstract

Introduction: Tumor necrosis factor receptor-associated factor 2 (TRAF2) participates in signaling of established pro-inflammatory cytokines such as CD40L and TNFα. Through its ability to activate JNK and inhibit apoptosis, TRAF2 potentially possesses several pro-atherogenic functions. Previously, we demonstrated overexpression of TRAF2 in human and Murine atherosclerotic lesions and dependency of pro-inflammatory gene expression on TRAF2 in atheroma-associated cell types. Here, we tested the hypothesis that TRAF2 deficiency decreases atherosclerosis in mice and evaluated potential correlations of its expression levels in blood with atherosclerosis and its complications in humans.

Methods and Results: Since homozygous TRAF2-deficient mice are not fully viable, fetal liver cell transplantations were performed. Lethally irradiated low-density lipoprotein receptor-deficient mice (LDLR−/− mice) were reconstituted with TRAF2-deficient or -competent fetal liver cells to test for the relevance of TRAF2 on hematopoieic cells. Additionally, TRAF2+/−/LDLR−/− mice received TRAF2-deficient fetal liver cells to gain at least some insight into the role of TRAF2 on resident cells. Transplantation efficacy proofed overall over 95% as assessed by the congenital markers CD45.1 and CD45.2. TRAF2-deficient chimera showed significantly lower levels of leukocytes before and after feeding while weights and cholesterol levels did not differ between the groups. Surprisingly, atherosclerotic lesion size did not differ between the three groups as assessed immunohistochemically in sections of the aortic root (N=18 per group). Similarly, no significant differences in cellular plaque composition could be observed, suggesting that TRAF2 does not modulate atherosclerosis in vivo. Accordingly, TRAF2/GAPDH ratios in total blood were similar between patients with ACS (0.0124±0.0011, N=70), CHD (0.00145±0.0008, N=178), and those without CHD (0.0133±0.0011, N=70).

Conclusions: Our study demonstrates that TRAF2 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These surprising data argues against a role for TRAF2 in inflammatory signaling.